Cancer Evolvability Program (CEP) PROJECT SUMMARY Evolution of tumors, and evolution generally, occurs by variation and selection. Variation creates the ability to evolve (evolvability). Whereas conventional therapies kill cells or stop them from growing (are anti- proliferative), proposed novel interventions that would inhibit the ability to evolve promise new and fundamentally different ways to inhibit oncogenesis and thwart resistance. The Cancer Evolvability Program (CE) aims to understand the fundamental underlying molecular mechanisms that generate variation and so drive tumor evolution; to develop new molecular approaches and tools to advance cancer diagnosis and therapy; and to develop with other CCSG programs the conceptual and technical frameworks for translational cancer research. The CE Program encompasses two themes, which focus on the two basic routes that generate variation: (1) Intrinsic: Genome and Phenotypic Plasticity (mutation, genome rearrangement, recombination, epigenetic and stochastic protein and RNA variation); and (2) Extrinsic: Infectious Oncogenesis and Microbiome, in which introduction of foreign genes, proteins, RNAs, and other molecules and genetic programs by infectious agents (viruses, microbes, microbiome) promote (or prevent) oncogenesis. The CCSG supports this research program by providing key shared resources, particularly Cytometry and Cell Sorting, Integrated Microscopy, Genomic and RNA Profiling, and Proteomics; as well as administrative support for meetings, clubs and interest groups, and pilot funding and recruitment funds. The CE Program currently has 31 members from ten departments in two institutions. Thirty members have primary appointments at Baylor College of Medicine, one member has a primary appointment at the University of Texas and therefore is an adjunct member. The Cancer Evolvability Program currently has $9.6M in peer-reviewed funding (direct costs per annum), $2.6M from NCI and $1.5M in other peer reviewed funding mostly from the Cancer Prevention and Research Initiative of Texas (CPRIT). Most of this is in the form of R01 grants. Members of the Cancer Evolvability Program published a total of 452 cancer-related papers in the previous funding period: 28% were inter-programmatic, 13% were intra-programmatic, and 50% were ?inter-institutional? (collaborations outside the Dan L Duncan Cancer Center).